Tubulin is currently among the most attractive therapeutic targets in new drug design for the treatment of solid tumors.1c The heralded success of vincristine and taxol along with the promise of combretastatin A-4 (CA-4) prodrug and dolastatin 10, to name just a few, have firmly established the clinical efficacy of these antimitotic agents for cancer treatment.
An aggressive chemotherapeutic strategy toward the treatment of solid-tumor cancers continues to rely on the development of architecturally new and biologically more potent anti-tumor, anti-mitotic agents which mediate their effect through a direct binding interaction with tubulin. A variety of clinically-promising compounds which demonstrate potent cytotoxicity and antitumor activity are known to effect their primary mode of action through an efficient inhibition of tubulin polymerization.1 This class of compounds undergoes an initial interaction (binding) to the ubiquitous protein tubulin which in turn arrests the ability of tubulin to polymerize into microtubules which are essential components for cell maintenance and division.2 During metaphase of the cell cycle, the nuclear membrane is broken down and the cytoskeletal protein tubulin is able to form centrosomes (also called microtubule organizing centers) and through polymerization and depolymerization of tubulin the dividing chromosomes are separated. Currently, the most recognized and clinically useful members of this class of antimitotic, antitumor agents are vinblastine and vincristine3 along with taxol.4 Additionally, the natural products rhizoxin,5 combretastatin A-4 and A-2,6 curacin A,1 podophyllotoxin,7 epothilones A and B,8 dolastatin 109 and welwistatin10 (to name just a few) as well as certain synthetic analogues including phenstatin,11 the 2-styrylquinazolin-4(3H)-ones (SQO),12 and highly oxygenated derivatives of cis- and trans-stilbene13 and dihydrostilbene are all known to mediate their cytotoxic activity through a binding interaction with tubulin. The exact nature of this binding site interaction remains largely unknown, and definitely varies between the series of compounds. Photoaffinity labeling and other binding site elucidation techniques have identified several key binding sites on tubulin: colchicine site, vinca alkaloid site, and a site on the polymerized microtubule to which taxol binds.1a,14 